The present invention relates to methods for producing amino-2-imidazoline derivatives. More particularly, the invention relates to methods for producing such derivatives which effectively provide high yields of the desired product or products.
Amino-2-imidazoline derivatives have a variety of uses including, but not limited to, as cardiovascular anti-hypertension agents; as sedatives and analgesics; as agents for the treatment of drug and alcohol withdrawal symptoms; as diuretic agents; as antidiarrheal agents; as agents which lower intraocular pressure and as vasoconstrictors.
Amino-2-imidazoline derivatives have been synthesized by a number of methods which include the reaction of ethylenediamine with an N-substituted-methylisothionium iodide salt or with an N-substituted dichloroimino derivative; the coupling of alkyl or aryl amines with N-acetyl-2-imidazolidinone in the presence of POC13 followed by hydrolysis of the intermediate N-acetyl imidazoline; and the coupling of an alkyl or aryl amine with an S-alkyl-2-imidazoline. These methods have one or more drawbacks which include, for example, the use of harsh reagents such as POCl.sub.3 which can react with sensitive functional groups substituted on the amine; the release of noxious by-products such as alkyl mercaptans; sensitivity to steric hinderance; and relatively complex, multi-step processing schemes.
Maryanoff et al U.S. Pat. No. 4,656,291 discloses a process for the production of guanidines by reaction of an amidine sulfonic acid with ammonia, or a primary or secondary amine, or a cyclic amine having an NH group in a solvent, such as water, acetonitrile or a dipoar aprotic solvent, at a temperature up to the boiling point of the solvent. Further, this patent discloses that the anti-hypertensive clonidine, i.e., 2-(2,6-dichlorophenylamino)-2-imidazoline, can be synthesized by reacting the appropriate amidine sulfonic acid with ethylenediamine. The amidine sulfonic acid is produced by oxidizing a thiourea with hydrogen peroxide in the presence of a molybdenum catalyst at temperatures in the range of about 0.degree. C. to 80.degree. C., with a final oxidation temperature of about 15.degree. C. to 80.degree. C.
More effective, e.g., less hazardous and/or more economic, methods for producing amino-2-imidazoline derivatives would be advantageous. For example, increased yields of the desired derivative or derivatives would be a particularly useful benefit since overall processing would be reduced and the amounts of unwanted by-products would be decreased.